5-alkylpipecolic acids as anti-hypertensive agents

ABSTRACT

WHEREIN R IS C1-C8 ALKYL OR A SALT THEREOF TO SAID PATIENT.   2-(HOOC-),5-R1-PIPERIDINE   1. A METHOD OF LOWERING BLOOD PRESSURE IN HYPERTENSIVE PATIENT COMPRISING ADMINISTERING A THERAPEUTICALLY EFFECTIVE AMOUNT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE TRANS ISOMER AND A MIXTURE OF THE TRANS AND CIS ISOMERS REPRESENTED BY THE FORMULA

United States Patent 3,840,663 S-ALKYLPIPECOLIC ACIDS AS ANTI- HY PERTENSIVE AGENTS Peter Hadley Jones, Lake Forest, and Pitambar Somani,

Libertlylyille, 111., assignors to Abbott Laboratories, Chicago,

No Drawing. Filed Mar. 23, 1972, Ser. No. 237,527 Int. Cl. A61]: 27/00 US. Cl. 424-267 3 Claims ABSTRACT OF THE DISCLOSURE A method of lowering blood pressure in hypertensive patients comprising administering a therapeutically effective amount of a compound of the formula l \N o 0 OH wherein R is C -C alkyl or a salt thereof.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a method of treating hypertension using 5-alkylpipecolic acids as the antihypertensive agents.

5-Alkylpipecolic acids have previously been reported to be useful as intermediates in the preparation of certain quinolizidines, and as anesthetics and antibacterial agents. It has now been found that compounds of the formula lCOOH wherein R is C -C alkyl or a salt thereof are useful in lowering blood pressure in hypertensive patients.

As used herein, the term C -C alkyl refers to both straight and branched chain alkyl groups having from 1 to 8 carbon atoms, and including methyl, ethyl, npropyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl and the like.

The term salts refers to salts such as the alkali metal, alkaline earth metal, ammonium and substituted ammonium salts including the sodium, potassium, lithium, calcium, magnesium, barium, methyl ammonium, diethylammonium, benzylammonium, triethanol ammonium salts and the like, as well as the pharmaceutically acceptable acid addition salts including the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate and the like. Such salts are prepared by methods well known in the art.

The synthesis of the S-alkylpipecolic acids is disclosed in French Patent No. M1599 1963) and in Arch. Pharm. (Weinheim) 301 (10); 728-35 (1968).

The compounds useful in the practice of this invention have been separated into the cisand trans-isomers While the mixture and the trans-isomers exhibit antihypertensive activity, the cis-isomers are inactive as antihypertensive agents.

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The antihypertensive activity of the compounds useful in the practice of this invention was first established in the spontaneously hypertensive rat procedure, Tabei et al.,

Clin. Pharmac. Therap., 11 (2); 269-274 (1970), wherein significant decreases in blood pressure were observed at oral dosages of 10 mg./kg. of body weight and I at 30 mg./kg. i.p.

The compounds useful in the practice of this invention exhibit activity by both the oral and intraperitioneal routes; however, the oral route is the preferred route of administration. Accordingly, the compounds of this invention are administered to hypertensive patients at dosages of from 0.1 to mg./kg. of body weight daily, preferably in divided doses, i.e., three to four times daily.

The presently preferred compound is dl-trans-S-n-butylpipecolic acid which reduced blood pressure in spontaneously hypertensive rats up to 18% for 28 hours after oral administration of 10 mg./kg. dose. However, other suitable agents useful in the practice of this invention include S-methylpipecolic acid, S-n-propylpipecolic acid, S-neopentylpipecolic acid, S-n-hexylpipecolic acid and the like.

As is the case with other antihypertensive agents, the 5-alkylpipecolic acids can be co-administered with, for example, diuretics or tranquilizers.

While the compounds can be administered alone, that is, as the sole component of a filled capsule, it is preferred to formulate the compound in various dosage forms for oral or parenteral administration such as tablets, syrups, sterile aqueous or non-aqueous suspensions and the like. The oral dosage forms are prepared by methods well known in the art, and generally include a pharmaceutically acceptable carrier or diluent such as lactose, starch or sucrose, along with lubricating agents such as magnesium stearate and flavoring and sweetening agents and the like. The dosage forms for parenteral administration are also prepared by methods well known in the art.

We claim:

1. A method of lowering blood pressure in hypertensive patient comprising administering a therapeutically effective amount of a compound selected from the group consisting of the trans isomer and a mixture of the trans and cis isomers represented by the formula J COOH wherein R is C -C alkyl or a salt thereof to said patient. 2. The method of Claim 1 wherein said compound is S-n-butylpipecolic acid.

3. The method of Claim 1 wherein said compound is dl-trans-S-n-butylpipecolic acid.

References Cited Clin. Pharmac. & Therap., 11(2); 269-274 (1970).

ALBERT T. MEYERS, Primary Examiner D. M. STEPHENS, Assistant Examiner US. Cl. X.R. 424263 Patented Oct. 8, 197 4 

1. A METHOD OF LOWERING BLOOD PRESSURE IN HYPERTENSIVE PATIENT COMPRISING ADMINISTERING A THERAPEUTICALLY EFFECTIVE AMOUNT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE TRANS ISOMER AND A MIXTURE OF THE TRANS AND CIS ISOMERS REPRESENTED BY THE FORMULA 